1. Field of the Invention
The present invention relates to a copolymer that can be used as an antithrombotic surface treating agent and to an antithrombotic surface treating agent comprising such a copolymer. Also, the present invention relates to a medical apparatus and tool the surface of which is treated with the antithrombotic surface treating agent described above and to a method for producing such a medical apparatus or tool.
2. Description of the Related Art
Recently, studies on medical materials utilizing various polymer materials has been in progress and their application to blood filters, membranes for dialyzer, membranes for blood plasma separator, catheters, membranes for oxygenator, artificial blood vessels, membranes for preventing accretion, artificial skin or the like is expected. In this case, synthetic materials that are foreign materials to organisms are used in contact with tissues or blood in the organism so that the medical material must have biocompatibility.
Where a medial material is used as a material to be contacted with blood, the following three elements are important items of its biocompatibility: (a) inhibition of the blood coagulation system, (b) inhibition of the adhesion and activation of platelets, and (c) inhibition of activation of the complement system.
In particular, where it is used as a material to be contacted with blood only for a relatively short time, such as a medical material for extracorporeal circulation (for example, dialyzer, membrane of blood plasma separator, etc.), generally an anticoagulating agent such as heparin or sodium citrate is simultaneously used. Accordingly, the inhibition of activation of platelets and complement system as in (b) and (c) described above are important problems.
Regarding (b) the inhibition of the adhesion and activation of platelets above, it has been reported that a surface with micro phase separation or a hydrophilic surface, in particular a gelled surface having bonded thereon a water-soluble polymer is superior but a hydrophobic surface such as a surface of polypropylene is inferior (see, for example, Trans. Am. Soc. Artif. Intern. Organs, Vol. XXXIII, p. 75-84 (1987) and Polymers and Remedy, Mita Publishing Association, p. 73 (1989)).
Although the surface having a micro phase separation structure can exhibit good blood compatibility by controlling it to a suitable phase separation state, the conditions under which such a phase separation state can be made are limited and the material finds a limited application. The gelled surface having bonded thereon a water-soluble polymer can inhibit the adhesion of platelets. However, the platelets activated on the surface of the material and fine thrombi are returned into the body, which frequently causes the problem of extraordinary variation of blood cells (platelets).
Tsuruta et al. have proposed a polymer having a basic nitrogen containing functional group and a nitrogen content of 0.05 to 3.5% by weight as a surface to which platelets hardly adhere (Japanese Patent Application Laid-open Nos. 60-119955, 60-119956, and 60-119957). However, the polymer is based on HEMA (2-hydroxyethyl methacrylate) so that a problem arises that the activation of complement system takes place.
On the other hand, regarding (c) activation of the complement system, it is known that the surface of material having a hydroxyl group, such as cellulose or ethylene-vinyl alcohol copolymer, shows a high activity but a hydrophobic surface such as the surface of polypropylene shows a weak activity (see, for example, Artificial Organs 16(2), p. 1045-1050 (1987)).
Therefore, use of materials based on cellulose and vinyl alcohol, respectively in for example membranes for artificial organs causes the problem of activation of the complement system. On the contrary, use of hydrophobic surfaces such as the surface of polyethylene causes the problem of adhesion and activation of platelets.
Furthermore, where the medical material is used as a material to be contacted with blood for a relatively long time as in the case of an artificial blood vessel, it must be a material having affinity for the tissues (cells) in an organism in addition to the above 3 items so that neoplastic tunica intima formation and neogenesis and regeneration of tissues in the organism can take place suitably. The material for an artificial blood vessel includes, for example, ultra fine polyester fiber (Artificial Organs 19(3), p. 1287-1291 (1990)). The ultra fine polyester fiber is one of medical materials that utilize recognition of foreign matter by the organism, cure of wounds by biophylaxis, and self-to-self tissue regeneration, and is currently used mainly as an artificial blood vessel.
However, a prolonged application of the artificial blood vessel to microvessels causes the problem of their occlusion.
Moreover, for medial materials that contact tissues or fluid in the organism as well as blood, for example, membrane for preventing accretion and implanting material, which are implanted in the organism for a long period of time, or wound covering material used in contact with wounded portion (site where the skin is peeled and damaged to expose the tissue in the organism), a surface that is recognized by the organism as a foreign matter in few occasions and is readily peeled off from the organism (no accreting surface) is necessary.
However, in the case of silicone, polyurethane and polytetrafluoroethylene used as the above-described material, no satisfactory properties have been obtained yet since the tissue in the organism coalesce with the surface of the material or the recognition of it as a foreign matter by the organism is too intense.
Therefore, no polymer surface that satisfies simultaneously the biocompatibilities required for medical materials used in contact with the tissues in the organism or blood, such as inhibition of adhesion and activation of platelets, inhibition of activation of complement system and affinity for the tissues in the organism, has been obtained yet.
On the contrary, the present inventors have found that specified alkoxyalkyl (meth)acrylate polymer is excellent in antithrombosis and further in biocompatibility and proposed as a medical material (Japanese Patent Application Laid-open No. Hei 4-152952 (Japanese Patent No. 2806510) and Japanese Patent Application Laid-open No. Hei 5-262656).
However, the surface treated with these polymers is hydrophobic so that its application is limited and cannot be used for a variety of uses.
An object of the present invention is to provide a copolymer that is superior in antithrombotic property and further biocompatibility to the conventional medical materials and can be used as a medical material having high hydrophilicity.
Another object of the present invention is to provide a surface treating agent comprising such a copolymer.
Still another object of the present invention is to provide a medical apparatus having a surface treated with such an antithrombotic surface treating agent.
Yet another object of the present invention is to provide a method for producing such a medical apparatus.
The present inventors have made extensive studies with a view to solving the above problems and as a result they have found that a copolymer comprising a specified alkoxyalkyl (meth)acrylate and a monomer having a basic functional group copolymerizable with the specified monomer as monomer components and having a specified molar ratio of one to the other has antithrombotic property equivalent to or higher than and hydrophilicity higher than the conventional alkoxyalkyl (meth)acrylate homopolymer or the like. The present invention is based on this discovery.
That is, in accordance with a first embodiment of the present invention, there is provided a copolymer comprising a monomer of formula (1) below and a monomer having a basic functional group copolymerizable with the monomer as monomer components, wherein molar ratio of the monomer of formula (1) to the monomer having a basic functional group is 85/15 to 99.9/0.1 and wherein the copolymer has a number based mean molecular weight of 5,000 to 500,000. 
(wherein R1 is an alkylene group having 1 to 4 carbon atoms, R2 is an alkyl group having 1 to 4 carbon atoms, and R3 represents hydrogen or a methyl group).
It is preferred that the monomer of formula (1) is 2-methoxyethyl (meth)acrylate.
In one of preferred modes, the monomer having a basic functional group comprises at least one monomer selected from the group consisting of monomers of formulae (2), (3), (4) and (5), respectively. 
(wherein (R4)s independently represent hydrogen or an alkyl group having 1 to 4 carbon atoms, (R5)s independently represent hydrogen or a methyl group, n is an integer of 1 to 4, and (Xxe2x88x92)s independently represent an anion derived from halogen, sulfonic acid or sulfuric acid)
It is preferred that the monomer of formula (2) is at least one monomer selected from the group consisting of N,N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, and N,N-diethylaminoethyl (meth)acrylate.
The monomer of formula (3) is preferably at least one monomer selected from N,N-dimethylaminopropylmethacrylamide and N,N-dimethylaminopropylacrylamide.
In one of preferred modes, the monomer having a basic functional group is at least one monomer selected from the group consisting of aminostyrene, N,N-dimethylaminostyrene, N,N-diethylaminostyrene, vinylpyridine, N-methyl-N-vinylpyridine, N-ethyl-N-vinylpyridine, vinylquinoline, ethyleneimine, propyleneimine, N-aminoethylethyleneimine, vinylimidazole, vinylpyrazoline, and vinylpyrazine.
In accordance with a second embodiment of the present invention, there is provided an antithrombotic surface treating agent, comprising the copolymer described above.
In accordance with a third embodiment of the present invention, there is provided a medical apparatus having a surface treated with the antithrombotic surface treating agent described above.
Preferably, the surface of the medical apparatus is made of polyurethane or polyester.
As the medical apparatus, a blood filter is one of preferred modes.
In accordance with a fourth embodiment of the present invention, there is provided a method for producing a medical apparatus, comprising the steps of: coating the antithrombotic surface treating agent described above on a surface of a medical apparatus, and heat-drying the agent.
The copolymer of the present invention is excellent in antithrombotic property and further in biocompatibility and can be used as a medical material having a high hydrophilicity.
The antithrombotic surface treating agent of the present invention comprising the copolymer of the invention can be advantageously used for the surface treatment of a medical apparatus such as a blood circuit or a membrane for an artificial organ.
The medical apparatus of the present invention has a surface treated with the antithrombotic agent of the invention so that it is excellent in antithrombotic property and further in biocompatibility.
The blood filter of the present invention comprises a filter whose surface is treated with the antithrombotic surface treating agent of the invention, so that it is excellent in antithrombotic property and can recover platelets efficiently.
The method for producing a medical apparatus according to the present invention can increase the adhesion between the filter and the copolymer of the present invention to fix the copolymer to the filter more firmly.
The copolymer in accordance with the first embodiment of the present invention comprises as monomer components a monomer of the formula (1) above (hereinafter, also referred to as xe2x80x9calkoxyalkyl (meth)acrylatexe2x80x9d) and a monomer having a basic functional group copolymerizable with the monomer of the formula (1) above. Here, xe2x80x9c(meth)acrylatexe2x80x9d stands for acrylate and methacrylate.
In the formula (1) above, R1 is an alkylene group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 or 2 carbon atoms, R2 is an alkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 or 2 carbon atoms, and R3 represents hydrogen or a methyl group.
The alkoxyalkyl (meth)acrylate includes, for example, methoxymethyl (meth)acrylate, methoxyethyl (meth)acrylate, methoxypropyl (meth)acrylate, methoxybutyl (meth)acrylate, ethoxymethyl (meth)acrylate, ethoxyethyl (meth)acrylate, ethoxypropyl (meth)acrylate, ethoxybutyl (meth)acrylate, propoxymethyl (meth)acrylate, propoxyethyl (meth)acrylate, propoxypropyl (meth)acrylate, propoxybutyl (meth)acrylate, and the like. These monomers may be used alone or two or more thereof may be used in combination.
Among the above monomers, methoxyalkyl (meth)acrylates are preferred from the viewpoints of economy and ease of manipulation. In particular, 2-methoxyethyl (meth)acrylate is preferred.
The monomer having a basic functional group described above is not particularly limited as far as it can copolymerize with the alkoxyalkyl (meth)acrylates described above.
Examples of the basic functional group include primary amino groups, secondary amino groups, tertiary amino groups, quaternary ammonium salts, a pyridyl group, an aziridine group, and an imidazolyl group.
In the present invention, according to one of preferred modes, the comonomer having the basic functional group described above (monomer that can copolymerize with the alkoxyalkyl (meth)acrylate) comprises at least one monomer selected from the group consisting of the monomers of the formulae (2), (3), (4) and (5) above.
In the formulae (2) to (5) above, (R4)s independently represent hydrogen or an alkyl group having 1 to 4 carbon atoms, preferably hydrogen or an alkyl group having 1 or 2 carbon atoms, and more preferably hydrogen or a methyl group, (R5)s independently represent hydrogen or a methyl group, n is an integer of 1 to 4, and (Xxe2x88x92)s independently represent an anion derived from halogen, sulfonic acid or sulfuric acid. The anion derived from sulfuric acid includes hydrogen sulfate ion and sulfate ion.
The monomer of the formula (2) above includes aminoalkyl (meth)acrylates. Specific examples thereof include, for example, aminomethyl (meth)acrylate, aminoethyl (meth)acrylate, aminoisopropyl (meth)acrylate, amino-n-butyl (meth)acrylate, N-methylaminoethyl (meth)acrylate, N-ethylaminoisobutyl (meth)acrylate, N-isopropylaminomethyl (meth)acrylate, N-isopropylaminoethyl (meth)acrylate, N-n-butylaminoethyl (meth)acrylate, N-t-butylaminoethyl (meth)acrylate, N,N-dimethylaminomethyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, N,N-dimethylaminobutyl (meth)acrylate, N-methyl-N-ethylaminoethyl (meth)acrylate, N-methyl-N-butylaminoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-diethylaminopropyl (meth)acrylate, N,N-dipropylaminoethyl (meth)acrylate, N,N-dipropylaminopropyl (meth)acrylate, and N,N-diaminobutylpropyl (meth)acrylate.
The monomer of the formula (3) above includes aminoalkyl (meth)acrylamides. Specific examples thereof include, for example, aminomethyl (meth)acrylamide, aminoethyl (meth)acrylamide, aminoisopropyl (meth)acrylamide, amino-n-butyl (meth)acrylamide, N-methylaminoethyl (meth)acrylamide, N-ethylaminoisobutyl (meth)acrylamide, N-isopropylaminomethyl (meth)acrylamide, N-isopropylaminoethyl (meth)acrylamide, N-n-butylaminoethyl (meth)acrylamide, N-t-butylaminoethyl (meth)acrylamide, N,N-dimethylaminomethyl (meth)acrylamide, N,N-dimethylaminoethyl (meth)acrylamide, N,N-dimethylaminopropyl (meth)acrylamide N,N-dimethylaminobutyl (meth)acrylamide, N-methyl-N-ethylaminoethyl (meth)acrylamide, N-methyl-N-butylaminoethyl (meth)acrylamide, N,N-diethylaminoethyl (meth)acrylamide, N,N-diethylaminopropyl (meth)acrylamide, N,N-dipropylaminoethyl (meth)acrylamide, N,N-dipropylaminopropyl (meth)acrylamide, N,N-diaminobutylpropyl (meth)acrylamide and the like.
The monomers of the formulae (4) and (5) above are each derivatives obtained by treating the monomers of the formulae (2) and (3) above, respectively, with an alkyl halide, an alkyl sulfate or the like to convert them into quaternary ammonium salts.
In the present invention, according to one of preferred modes, the comonomer having a basic functional group comprises at least one monomer selected from the group consisting of aminostyrene, N,N-dimethylaminostyrene, N,N-diethylaminostyrene, vinylpyridine, N-methyl-N-vinylpyridine, N-ethyl-N-vinylpyridine, vinylquinoline, ethyleneimine, propyleneimine, N-aminoethylethyleneimine, vinylimidazole, vinylpyrazoline, and vinylpyrazine.
According to one of preferred modes, the comonomer having a basic functional group may comprise at least one derivative obtained by treating these monomers with an alkyl halide, an alkyl sulfate or the like to convert them into quaternary ammonium salts thereof.
The comonomers having a basic functional group may be used alone or two or more of them may be used in combination.
Particularly preferred comonomers among those described above are N,N-dialkylaminopropyl (meth)acrylamides corresponding to the formula (3) in which n is 3, which are easy to synthesize on an industrial scale and inexpensive, with N,N-dimethylaminopropyl methacrylamide and/or N,N-dimethylaminopropyl acrylamide being particularly preferred.
Also, the monomers of the formula (2) above in which n is 2 or 3 are preferred, in particular, at least one selected from the group consisting of N,N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate and N,N-diethylaminoethyl (meth)acrylate is preferred.
The copolymer of the present invention comprising as monomer components the monomer of the formula (1) above and the monomer having a basic functional group above is characterized in that the molar ratio of the monomer of the formula (1) above to the monomer having a basic functional group is 85/15 to 99.9/0.1.
By setting the molar ratio of the monomer of the formula (1) above to the monomer having a basic functional group within the above range, the copolymer of the present invention when used as a surface treating agent can have antithrombotic property equivalent or superior to and hydrophilicity superior to the case where the homopolymer of the monomer of the formula (1) above is used.
The molar ratio of the monomer of the formula (1) above to the monomer having a basic functional group is preferably 90/10 to 99/1 and more preferably 95/5 to 98/2.
The copolymer of the present invention has a number based average molecular weight of preferably 5,000 to 500,000 and more preferably 50,000 to 200,000. When the number based average molecular weight is in the above range, the elution thereof into blood or its cytotoxicity can be decreased.
The copolymer of the present invention may be any one of random copolymer, block copolymer and graft copolymer. The copolymerization reaction for producing the copolymer of the present invention is not particularly limited and any known method such as radical polymerization, ion polymerization, photo polymerization, polymerization using a macromer or the like may be employed.
The copolymer of the present invention as described above is insoluble in water and can be used as a surface treating agent.
In accordance with the second embodiment, the present invention relates to an antithrombotic surface treating agent comprising the copolymer described above.
The antithrombotic surface treating agent of the invention may comprise any one of the copolymers of the present invention or two or more of them in admixture.
The antithrombotic surface treating agent of the present invention is excellent in antithrombotic property and further in biocompatibility so that it can be advantageously used in surface treatment of medical apparatus and membranes for use in artificial organs.
In particular, the antithrombotic surface treating agent of the present invention is superior in hydrophilicity to the homopolymer of the monomer of the formula (1) above and hence it can be used in a variety of applications. For example, it can be used for various base materials that are subjected to be surface treatment. Examples of hydrophilic base material include polyurethane, cellulose, polyamide, poly(meth)acrylate, natural polymers (for example, cotton, hemp, etc.), and the like and examples of hydrophobic base material include polypropylene, polycarbonate, polyester, polyvinyl chloride, polysulfone, and polyacrylonitrile, and the like. These materials may be selected suitably depending on the purpose. Among them, preferred base materials include polyurethane, polypropylene, polycarbonate, polyester, and polyvinyl chloride.
The surface treated with the antithrombotic surface treating agent of the present invention is hydrophilic. Therefore, it has excellent wettability to the body fluid such as blood. For example, it is advantageous in that when the surface of blood circuit or membrane for artificial organ is treated to have such a surface, foams hardly attach to the surface.
The surface treated with the antithrombotic surface treating agent of the present invention has a contact angle of water of preferably 36 to 60 degrees, more preferably 38 to 50 degrees.
In accordance with the third embodiment, the present invention relates to a medical apparatus having a surface treated with the antithrombotic surface treating agent of the present invention. The medical apparatus of the present invention is treated with the antithrombotic surface treated agent of the present invention over at least a portion of the surface, preferably over its entire surface that contacts blood or the like.
The medical apparatus of the present invention is the one of which excellent antithrombotic property is required according to one of preferred modes. Examples of such a medical apparatus include a blood filter, a blood storage bag, a blood circuit, an indwelling needle, a catheter, a guide wire, a stent, an oxygenator, a dialyzer, a coalescence preventing material, a wound covering material, an adhesive for tissues, and a repairing material for tissue regeneration. In particular, according to a preferred mode, the medical apparatus of the present invention has an extracorporeal circulation circuit having a blood contact portion therein.
The medical apparatus of the present invention preferably has a polyurethane or polyester surface treated with the antithrombotic surface treating agent of the present invention. when the surface is constituted by polyurethane or polyester, the layer treated with the antithrombotic surface treating agent of the present invention (the film of the copolymer of the present invention) hardly is peeled off.
Among those described above as preferred medical apparatuses of the present invention, the blood filter is one of the particularly preferred modes.
The blood filter of the present invention comprises a filter material in which at least a portion, preferably the whole of the surface thereof is treated with the antithrombotic surface treating agent of the present invention. Here, the surface of a filter means the both surfaces of the filter on which blood contacts and surface portion of the pores in the filter.
The shape of the blood filter of the present invention is not particularly limited. For example, it may be in the form of a porous material, a thread, a nonwoven fabric, particles, a film, a sheet, a tube, a hollow fiber, or powder. Among them, a porous material and a nonwoven fabric are preferred.
In the case of a porous material, it has a mean flow pore diameter of preferably 1 to 20 xcexcm measured using a perm porosimeter. If the mean flow pore diameter is below 1 xcexcm, the filter tends to be clogged while if it is above 20 xcexcm, the removal ratio of leukocyte described below may sometimes decrease to 50% or less.
The material of the blood filter of the present invention includes, for example, natural polymers such as cotton and hemp; synthetic polymers such as nylon, polyester, polyacrylonitrile, polyolefin, halogenated polyolefin, polyethylene terephthalate, polyurethane, polyamide, polysulfone, polyethersulfone, poly(meth)acrylate, ethylene-polyvinyl alcohol copolymer and butadiene-acrylonitrile copolymer; and mixtures of these.
In particular, when the blood filter of the present invention is made in the form of a porous material, it is preferred that polyurethane be used and when it is made in the form of a nonwoven fabric, use of polyethylene terephthalate is preferred.
The blood filter of the present invention is a filter that is used for removing leukocytes from the liquid containing platelets and leukocytes and is used mainly in the preparation, treatment, etc., for blood products such as platelet preparation, with targeting whole blood, platelet concentrate (PC), platelet rich plasma (PRP), and the like.
The blood filter of the present invention can be used as a cell separation filter such as a filter for collecting hematopoietic stem cells.
The filter incorporated in the blood filter of the present invention includes, for example, sponge-like, porous, nonwoven fabrics comprising polyester fiber. The filter is treated with the antithrombotic surface treating agent of the present invention on its surface to bear the copolymer of the present invention on the surface thereof.
The method for having the copolymer of the present invention carried on the surface of the filter includes known methods such as a coating method; a method using graft polymerization with radiation, electron beam or ultraviolet rays; and a method using a chemical reaction with the functional group of a base material. Among them, the coating method is practically preferred since it is simple in production step.
The application method is not particularly limited, and any of a coating method, a spraying method, a dipping method and the like may be used.
For example, the application of the copolymer of the present invention by a dipping coating method may be practiced by a simple operation such as by dipping a filter in a coating solution comprising a suitable organic solvent such as alcohol, chloroform, acetone, tetrahydrofuran or dimethylformamide having dissolved therein the antithrombotic surface treating agent of the present invention, removing excessive solution, and then air-drying the filter.
It is preferred that the filter after coating be heated to dry it. This increases the adhesion between the filter and the copolymer of the present invention to thereby fix the copolymer to the filter more firmly.
The treating method described above is not limited to the case where the medical apparatus of the present invention is a blood filter but can be applied to all the medical apparatuses. That is, the present invention provides a method for producing a medical apparatus, comprising the steps of coating the antithrombotic surface treating agent of the present invention on a surface of a medical apparatus, and heat-drying the agent.
The blood filter of the present invention has a leukocyte removal ratio of preferably 99% or more and more preferably 99.5% or more.
The blood filter of the present invention can realize high bleeding out rate and high filtration rate because of excellent blood compatibility and wettability to blood of the copolymer of the present invention.
Also, the blood filter of the present invention can be readily controlled of its leukocyte adsorbability by suitably changing the composition and ratio of the comonomer having a basic functional group that constitutes the copolymer.
Further, the blood filter of the present invention exhibits high removal rate for leukocytes and shows less activation of blood components such as blood bradykinin increase, so that it will not decrease the quality of blood after the filtration.
Furthermore, the blood filter of the present invention exhibits high platelet recovery ratio and the blood after the filtration does not cause hemolysis so that it is excellent in long-term storage of blood.